Cancer is a serious health problem across the world. It is estimated that 7.6 million people in the world died of cancer in 2007. In the UK for example, cancer is responsible for 126,000 deaths per year. One in four people die from cancer.
Known treatments for cancer include surgery, chemotherapy and radiotherapy. Many cancers can be cured if detected early enough.
100 years ago, the concept of antibodies as “magic bullets” was proposed by the German chemist Paul Ehrlich. Antibodies are capable of recognising and binding to their antigens in a specific manner and are therefore ideal agents for recognizing and destroying malignant cells via the immune system. For this reason, they constitute the most rapidly growing class of human therapeutics for cancer.
A number of potential cancer or tumour markers and cancer antigens have been identified in the literature and antibody therapies have been developed against some of them.
For example, the well-known cancer therapy Herceptin (Trastuzumab) is a monoclonal antibody that can kill HER2-positive cancer cells. Herceptin binds to the HER2 (human epidermal growth factor receptor 2) antigen on the cancer cell. Likewise, Bevacizumab (Avastin™) is a monoclonal antibody targeted against vascular endothelial growth factor (VEGF), one of the growth factors implicated in the formation of new blood vessels. By inhibiting angiogenesis, Bevacizumab prevents tumour cells from receiving a constant supply of blood to receive the oxygen and nutrients the tumour needs to survive.
However, the applicability of antibody therapeutics for different cancers is not universal. One of the limitations that has prevented the general use of antibody therapeutics is the large size of antibody molecules and their consequent inability to cross the plasma or cell membrane. In the absence of modification, antibodies (including monoclonal antibodies) are only generally suitable for targeting cancer antigens located at the surface or exterior of host cells14-15. In the examples above, HER2 receptor is located on the cell surface and is hence accessible for antibody binding by Herceptin. Likewise, VEGF is secreted into the bloodstream and is able to be bound by Bevacizumab.
PRLs are intracellular C-terminally prenylated proteins. Mutant forms of PRLs that lack the prenylation signal are often localized in nuclei16-17. The localization of PRL-1 and PRL-3 to the inner leaflet of the plasma membrane and early endosomes was revealed by EM immunogold labeling18. Over-expression of PRL-3 and PRL-1 has been shown to be associated with a variety of human cancers3-12,19. PRL-1 and PRL-3 are known to be associated with tumour metastasis. It is known that most cancer patients die from metastases and not from their primary disease.
There is an urgent need for effective ways of preventing cancer metastasis. Antibodies have not hitherto been used for targeting intracellular antigens or cancer markers because of the inability of the antibodies to cross the cell membrane and the consequent inaccessibility of the antigen.